2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide (7), (which is hereinafter referred to as “copanlisib”), is a proprietary cancer agent with a novel mechanism of action, inhibiting Class I phosphatidylinositol-3-kinases (PI3Ks). This class of kinases is an attractive target since PI3Ks play a central role in the transduction of cellular signals from surface receptors for survival and proliferation. Copanlisib exhibits a broad spectrum of activity against tumours of multiple histologic types, both in vitro and in vivo.
Copanlisib may be synthesised according to the methods given in international patent application PCT/EP2003/010377, published as WO 04/029055 A1 on Apr. 8, 2004, (which is incorporated herein by reference in its entirety), on pp. 26 et seq.
Copanlisib is published in international patent application PCT/US2007/024985, published as WO 2008/070150 A1 on Jun. 12, 2008, (which is incorporated herein by reference in its entirety), as the compound of Example 13: 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide.
Copanlisib may be synthesized according to the methods given in WO 2008/070150, pp. 9 et seq., and on pp. 42 et seq. Biological test data for said compound of formula (I) is given in WO 2008/070150 on pp. 101 to 107.
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimid-azo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride (8), (which is hereinafter referred to as “copanlisib dihydrochloride”) is published in international patent application PCT/EP2012/055600, published as WO 2012/136553 on Oct. 11, 2012, (which is incorporated herein by reference in its entirety), as the compound of Examples 1 and 2: 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride: it may be synthesized according to the methods given in said Examples 1 and 2.
Copanlisib may exist in one or more tautomeric forms: tautomers, sometimes referred to as proton-shift tautomers, are two or more compounds that are related by the migration of a hydrogen atom accompanied by the migration of one or more single bonds and one or more adjacent double bonds.
Copanlisib may for example exist in tautomeric form (Ia), tautomeric form (Ib), or tautomeric form (Ic), or may exist as a mixture of any of these forms, as depicted below. It is intended that all such tautomeric forms are included within the scope of the present invention.

Copanlisib may exist as a solvate: a solvate for the purpose of this invention is a complex of a solvent and copanlisib in the solid state. Exemplary solvates include, but are not limited to, complexes of copanlisib with ethanol or methanol.
Copanlisib may exist as a hydrate: Hydrates are a specific form of solvate wherein the solvent is water.
As mentioned supra, copanlisib is, in WO 2008/070150, described on pp. 9 et seq., and may be synthesized according to the methods given therein on pp. 42 et seq., viz.:

In Reaction Scheme 1, vanillin acetate can be converted to intermediate (III) via nitration conditions such as neat fuming nitric acid or nitric acid in the presence of another strong acid such as sulfuric acid. Hydrolysis of the acetate in intermediate (III) would be expected in the presence of bases such as sodium hydroxide, lithium hydroxide, or potassium hydroxide in a protic solvent such as methanol. Protection of intermediate (IV) to generate compounds of Formula (V) could be accomplished by standard methods (Greene, T. W.; Wuts, P. G. M.; Protective Groups in Organic Synthesis; Wiley & Sons: New York, 1999). Conversion of compounds of formula (V) to those of formula (VI) can be achieved using ammonia in the presence of iodine in an aprotic solvent such as THF or dioxane. Reduction of the nitro group in formula (VI) could be accomplished using iron in acetic acid or hydrogen gas in the presence of a suitable palladium, platinum or nickel catalyst. Conversion of compounds of formula (VII) to the imidazoline of formula (VIII) is best accomplished using ethylenediamine in the presence of a catalyst such as elemental sulfur with heating. The cyclization of compounds of formula (VIII) to those of formula (IX) is accomplished using cyanogen bromide in the presence of an amine base such as triethylamine, diisopropylethylamine, or pyridine in a halogenated solvent such as DCM or dichloroethane. Removal of the protecting group in formula (IX) will be dependent on the group selected and can be accomplished by standard methods (Greene, T. W.; Wuts, P. G. M.; Protective Groups in Organic Synthesis; Wiley & Sons: New York, 1999). Alkylation of the phenol in formula (X) can be achieved using a base such as cesium carbonate, sodium hydride, or potassium t-butoxide in a polar aprotic solvent such as DMF or DMSO with introduction of a side chain bearing an appropriate leaving group such as a halide, or a sulfonate group. Lastly, amides of formula (I) can be formed using activated esters such as acid chlorides and anhydrides or alternatively formed using carboxylic acids and appropriate coupling agents such as PYBOP, DCC, or EDCI in polar aprotic solvents.

In Reaction Scheme 2, a compound of formula (IV), prepared as described above, can be converted to a structure of formula (XII) using ammonia in the presence of iodine in an aprotic solvent such as THF or dioxane. Alkylation of the phenol in formula (XII) can be achieved using a base such as cesium carbonate, sodium hydride, or potassium t-butoxide in a polar aprotic solvent such as DMF or DMSO with introduction of a side chain bearing an appropriate leaving group such as a halide, or a sulfonate group. Reduction of the nitro group in formula (XIII) could be accomplished using iron in acetic acid or hydrogen gas in the presence of a suitable palladium, platinum or nickel catalyst. Conversion of compounds of formula (XIV) to the imidazoline of formula (XV) is best accomplished using ethylenediamine in the presence of a catalyst such as elemental sulfur with heating. The cyclization of compounds of formula (XV) to those of formula (XVI) is accomplished using cyanogen bromide in the presence of an amine base such as triethylamine, diisopropylethylamine, or pyridine in a halogenated solvent such as DCM or dichloroethane. Lastly, amides of formula (I) can be formed using activated esters such as acid chlorides and anhydrides or alternatively formed using carboxylic acids and appropriate coupling agents such as PYBOP, DCC, or EDCI in polar aprotic solvents.
The two already known synthetic pathways, Reaction Schemes 1 and 2, supra, suffer from numerous disadvantages which pose especially problems at larger scale:                Batchwise nitration of a molecule which is susceptible to oxidation is problematic for scale-up due to safety-concerns. For this reason, we developed a continuous process via microreaction-technology, as exemplified in Example 1 (vide infra).        Conversion of the aldehyde-group into a nitrile with ammonia and iodine as reagents is dangerous as ammonia and iodine may form nitrogen triiodide, a highly sensitive explosive substance.        The cyclisation with ethylenediamine to the imidazoline-ring needs sulfur. As sulfur is very difficult in cleaning processes in technical systems with fixed reactors and tubings, this cyclisation reaction is not suitable for scaleup.        Reduction of the nitro group to the corresponding amine on larger scale is difficult with iron and acid. Standard catalytic reductions often suffer from side reactions, e.g. imidazoline ring-opening which reduces the yield significantly.        
It was therefore desirable to devise a new synthesis, which circumvents these disadvantages and is suitable for production scale/industrial scale.
It has been very surprisingly discovered, and this provides the basis of the present invention, that compounds of the following structure-type, in particular copanlisib, can be synthesized according to the following scheme, see Reaction Scheme 3, infra:

First of all, the synthesis of the present invention, as depicted in Reaction Scheme 3, supra, does not need any protection chemistry which in general reduces the number of chemical steps needed at least by 2 steps (protection and deprotection). Of course, if needed or wanted, many sorts of protection chemistry are compatible with the new synthesis (Greene, T. W.; Wuts, P. G. M.; Protective Groups in Organic Synthesis; Wiley & Sons: New York, 1999).
More particularly, the following further advantages of the specific steps of the synthesis of the present invention, as depicted in Reaction Scheme 3, supra, are given infra:                Step A1: The nitration reaction is performed in a microreactor system, thereby the exothermic reaction is easily controlled and no danger of a runaway reaction is given. Kilogramme-quantities of 2-nitrovanillin can easily be prepared within days or a few weeks. The isolated material contains the undesired regioisomer 6-nitrovanillin in similar amounts as material produced by the batch nitration.        Step A2: Simple alkylation mediated by a base like potassium carbonate, high yield.        Step A3: Direct conversion of the aldehyde to the imidazoline in a one-pot reaction of cyclisation and oxidation with ethylenediamine and N-bromosuccinimide (abbreviated herein to “NBS”). This new sequence solves two issues, as it circumvents:                    a) the use of ammonia/iodine for the conversion of the aldehyde to the nitrile (safety concerns), and            b) the use of sulfur during the imidazoline synthesis (scale-up issue).                        Step A3 has no safety issues, and is easily scaleable.        Step A4: Reduction with hydrogen and a specially prepared catalyst. It consists of palladium and iron on charcoal. Elemental iron is essential, side-reactions are suppressed.        Step A5: No changes to the reagent. Crystallization of the crude product with e.g. isopropanol improves the quality of the isolated product significantly (compared to synthetic procedure described in WO 2008/070150 page 85) by removing by-product triethylamine hydrobromide.        Step A6: N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (abbreviated herein to “EDCI”) is used as coupling reagent.        Step A7: Advantages compared to synthesis described in WO 2008/070150 (page 59, intermediate B): substitution of sodium hydride with sodium methoxide for the reaction of methyl 3,3-dimethoxypropanoate with methyl formate, one-pot procedure from methyl 3,3-dimethoxypropanoate to crude 2-aminopyrimidin-5-carboxylic acid, therefore no need to isolate hygroscopic intermediate 3,3-dimethoxy-2-methoxycarbonylpropen-1-ol sodium salt, and easy purification of crude 2-aminopyrimidine-5-carboxylic acid via the dicyclohexylamine salt.        Step A8: Easy purification of copanlisib via dihydrochloride (dihydrochloride is the final product).        
Hence, in a first aspect, the present invention relates to a method of preparing copanlisib (7) via the following steps shown in Reaction Scheme 3, infra:

In an embodiment of the first aspect, the present invention relates to a method of preparing copanlisib (7)
comprising the following steps:
step A6:
wherein a compound of formula (6):

is allowed to react with a compound of formula (6b):
optionally in the presence of a catalyst, such as N,N-dimethyl-4-aminopyridine for example, optionally in the presence of a coupling agent, such as N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride for example, optionally in a solvent, such as N,N-dimethylformamide for example,
thereby providing copanlisib (7):

said compound of formula (6):

being prepared by the following step A5:
wherein a compound of formula (5):
is allowed to react, optionally in the presence of a base, such as triethylamine for example, with an annelating agent, such as cyanogen bromide for example, be optionally in a solvent, such as dichloromethane for example, thereby providing a compound of formula (6);
said compound of formula (5):

being prepared by the following step A4:
wherein a compound of formula (4):
is allowed to react with hydrogen in the presence of a 5% palladium/1% iron catalyst on carbon which is water-wetted, in a solvent, such as methanol for example, thereby providing a compound of formula (5),
said copanlisib of formula (7):
being optionally to copanlisib dihydrochloride (8) by being allowed to react with hydrogen chloride, optionally hydrochloric acid,
thereby providing copanlisib dihydrochloride (8):

In an embodiment of the first aspect, the present invention relates to a method of preparing copanlisib dihydrochloride (8):

comprising the following step A8:
wherein copanlisib, of formula (7):
is allowed to react with hydrogen chloride, optionally hydrochloric acid,
thereby providing copanlisib dihydrochloride (8):

In an embodiment of the first aspect, the present invention relates to a method of preparing copanlisib (7):

comprising the following step A6:
wherein a compound of formula (6):

is allowed to react with a compound of formula (6b):
optionally in the presence of a catalyst, such as N,N-dimethyl-4-aminopyridine for example, optionally in the presence of a coupling agent, such as N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride for example, optionally in a solvent, such as N,N-dimethylformamide for example,
thereby providing copanlisib (7):

In a further embodiment of the first aspect of the present invention, the above-mentioned compound of formula (6b):

is prepared by the following step A7:
wherein a compound of formula (6a):
is:                a) allowed to react with a base, such as sodium methoxide for example, optionally in a solvent, such as 1,4-dioxane for example, with heating, such as under reflux for example, then,        b) after cooling, such as to room temperature for example, adding methyl formate, then        c) adding guanidine hydrochloride, followed by heating, such as under reflux for example, then,        d) adding water and an aqueous solution of a base, such as sodium hydroxide for example, followed by heating, then,        e) adding an aqueous solution of a mineral acid, such as hydrochloric acid for example,        f) adding an amine, such as dicyclohexylamine for example, and filter, then        g) adding an aqueous solution of a strong base, such as sodium hydroxide, then        h) adding an aqueous solution of a mineral acid, such as hydrochloric acid for example        
thereby providing a compound of formula (6b):

In a further embodiment of the first aspect of the present invention, the above-mentioned compound of formula (6):

is prepared by the following step A5:
wherein a compound of formula (5):
is allowed to react, optionally in the presence of a base, such as triethylamine for example, with an annelating agent, such as cyanogen bromide for example, optionally in a solvent, such as dichloromethane for example, thereby providing a compound of formula (6).
In a further embodiment of the first aspect of the present invention, the above-mentioned compound of formula (5):

is prepared by the following step A4:
wherein a compound of formula (4):
is allowed to react with a reducing agent, such as hydrogen for example, optionally in the presence of a catalyst, such as a bimetallic catalyst such as palladium/iron on carbon for example, particularly 5% palladium/1% iron on carbon which is water-wetted, optionally dissolved in a solvent or in suspension in a solvent, such as methanol for example, thereby providing a compound of formula (5).
In a particular embodiment of the first aspect of the present invention, the above-mentioned compound of formula (5):

is prepared by the following step A4:
wherein a compound of formula (4):
is allowed to react with hydrogen in the presence of a 5% palladium/1% iron catalyst on carbon which is water-wetted, in suspension in a solvent, such as methanol for example, thereby providing a compound of formula (5).
In a further embodiment of the first aspect of the present invention, the above-mentioned compound of formula (4):

is prepared by the following step A3:
wherein a compound of formula (3):
is allowed to react with ethylenediamine, optionally in the presence of N-bromosuccinimide, optionally in a solvent, such as dichloromethane for example, thereby providing a compound of formula (4).
In a further embodiment of the first aspect of the present invention, the above-mentioned compound of formula (3):

is prepared by the following step A2:
wherein a compound of formula (2):
optionally in a solvent, such as acetonitrile for example, optionally in the presence of a base, such as potassium carbonate for example,
is allowed to react with a compound of formula (2a):
optionally in a solvent, such as acetonitrile for example, optionally with heating, such as under reflux for example,
thereby providing a compound of formula (3).
In a further embodiment of the first aspect of the present invention, the above-mentioned compound of formula (2):

is prepared by the following step A1
wherein a compound of formula (1):
                a) optionally in solution in a solvent, such as dichloromethane for example, is allowed to react with nitric acid and sulphuric acid, and then        b) adding a base, such as potassium carbonate for example, optionally in a solvent, such as methanol for example,        
thereby providing a compound of formula (2).
In a further embodiment of the first aspect, the present invention relates to a method of preparing copanlisib (7), wherein each of said steps A1, A2, A3, A4, A5, A6 and A7 as shown in Scheme 3, supra, are described supra.
In accordance with a second aspect, the present invention relates to intermediate compounds which are useful in the preparation of copanlisib (7) and copanlisib dihydrochloride (8).
In an embodiment of said second aspect, the present invention relates to a compound:

In an embodiment of said second aspect, the present invention relates to a compound:

In an embodiment of said second aspect, the present invention relates to a compound:

In an embodiment of said second aspect, the present invention relates to a compound:

In an embodiment of said second aspect, the present invention relates to a compound:

In an embodiment of said second aspect, the present invention relates to a compound:

In an embodiment of said second aspect, the present invention relates to a compound:

In an embodiment of said second aspect, the present invention relates to a compound:

In an embodiment of said second aspect, the present invention relates to a compound:

In accordance with a third aspect, the present invention relates to the use of the intermediate compounds of said second aspect for preparing copanlisib (7) and copanlisib hydrochloride (8).
In an embodiment of third second aspect, the present invention relates to the use of:
for preparing copanlisib (7) or copanlisib hydrochloride (8).
In an embodiment of third second aspect, the present invention relates to the use of:
for preparing copanlisib (7) or copanlisib hydrochloride (8).
In an embodiment of said third aspect, the present invention relates to the use of:
for preparing copanlisib (7) or copanlisib hydrochloride (8).
In an embodiment of said third aspect, the present invention relates to the use of:
for preparing copanlisib (7) or copanlisib hydrochloride (8).
In an embodiment of said third aspect, the present invention relates to the use of:
for preparing copanlisib (7) or copanlisib hydrochloride (8).
In an embodiment of said third aspect, the present invention relates to the use of:
for preparing copanlisib (7) or copanlisib hydrochloride (8).
In an embodiment of said third aspect, the present invention relates to the use of:
for preparing copanlisib (7) or copanlisib hydrochloride (8).
In an embodiment of said third aspect, the present invention relates to the use of:
for preparing copanlisib (7) or copanlisib hydrochloride (8).
In an embodiment of said third aspect, the present invention relates to a compound
for preparing copanlisib (7) or copanlisib hydrochloride (8).
Within the context of the present invention the term “solvent”, as optionally present in any reaction step of the method of the invention, is understood, as is by the person skilled in the art, as meaning any substance in which other materials dissolve to form a solution, such as, without being limited to: a polar solvent, such as a polar protic solvent, such as water, n-butanol, isopropanol, n-propanol, ethanol, methanol, or formic acid or acetic acid, etc., for example; a polar aprotic solvent, such as 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, acetone, acetonitrile, dimethylformamide, sulfolane, pyridine or dimethylsulphoxide, etc., for example; or a non-polar solvents, such as pentane, hexane, benzene, toluene, diethyl ether, methyl ethyl ketone, dichoromethane, chloroform, tetrachloromethane, ethyl acetate, etc., for example; or any mixture of the solvents listed above.
It is understood that any combination of the definitions given in the above-mentioned embodiments is possible within the context of the present invention.
The invention will be better understood upon reading the Examples below, which are provided as an illustration of the present invention. The Examples below in no way whatsoever constitute a limitation of the present invention as described in the present text and as defined in the claims appended hereto.